Fospropofol formulations

ABSTRACT

The present disclosure provides pharmaceutical compositions for oral administration of fospropofol, or pharmaceutically acceptable salts of fospropofol, as well as methods of oral administration of fospropofol.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 17/217,656, filed on Mar. 30, 2021, the entirety of which isincorporated by reference herein.

TECHNICAL FIELD

The present disclosure pertains to pharmaceutical compositions for oraladministration of fospropofol, or pharmaceutically acceptable salts offospropofol, as well as methods for oral administration of fospropofol.

BACKGROUND

Propofol (2,6-diisopropylphenol) is approved for use as an intravenous,short-acting anesthetic agent for inducing and maintaining anesthesia.Fospropofol disodium, a water-soluble, phosphono-O-methyl prodrug ofpropofol, was approved for use as an intravenous sedative, but itsmarketing has been discontinued.

While intravenous administration is useful for anesthesia applications,oral administration of fospropfol would be desirable for other uses.Oral dosing, however, requires a dosage form having adequatebioavailability with minimal subject-to-subject variability. There is aneed for dosage forms of fospropofol that are orally bioavailable withminimal inter-subject variability.

SUMMARY

The present disclosure provides pharmaceutical dosage forms for oraladministration comprising fospropofol or a pharmaceutically acceptablesalt of fospropofol, and a pharmaceutically acceptable acid.

The disclosure also provides methods of orally administeringfospropofol, or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, the method comprising orally co-administeringfospropofol, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable acid, to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the dissolution profiles of 600 mg fospropofol disodiumsalt acidified tablets in 300 mL of 0.1 N HC1 at 37° C.

FIG. 2 depicts the propofol plasma profile comparison of 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) without pentagastrin pretreatment; 600 mg fospropofol disodiumtablet with tartaric acid acidifier (Composition A3) withoutpentagastrin pretreatment; and a 1300 mg fospropofol disodium aqueoussolution (30 mg/mL) without pentagastrin pretreatment which propofolplasma concentration is normalized to 600 mg fospropofol disodium.

FIG. 3 depicts the propofol plasma profile comparison of 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) with pentagastrin pretreatment; and 600 mg fospropofol disodiumtablet control (i.e., no acidifier) with pentagastrin pretreatment.

FIG. 4 depicts the propofol plasma profile comparison of 600 mgfospropofol disodium tablet with tartaric acid acidifier (CompositionA3) without pentagastrin pretreatment; and 600 mg fospropofol disodiumtablet control (i.e., no acidifier) with pentagastrin pretreatment.

FIG. 5 depicts the fospropofol plasma profiles from 600 mg fospropofoldisodium tablet with ascorbic acid acidifier (Composition A2) and 600 mgfospropofol disodium control composition (i.e., HMPC capsules, noacidifier) in fasted and fed dogs.

FIG. 6 depicts the propofol plasma profiles from 600 mg fospropofoldisodium tablet with ascorbic acid acidifier (Composition A2) and 600 mgfospropofol disodium control composition (i.e., HMPC capsules, noacidifier) in fasted and fed dogs.

FIG. 7 compares the dissolution profile of the 600 mg fospropofoldisodium tablet with ascorbic acid acidifier (Composition A2) and 600 mg(3×200 mg) fospropofol disodium control composition (i.e., HMPCcapsules, no acidifier).

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present disclosure may be understood more readily by reference tothe following detailed description of desired embodiments and theexamples included therein. In the following specification and the claimsthat follow, reference will be made to a number of terms which have thefollowing meanings.

Unless indicated to the contrary, the numerical values should beunderstood to include numerical values which are the same when reducedto the same number of significant figures and numerical values whichdiffer from the stated value by less than the experimental error ofconventional measurement technique of the type described in the presentapplication to determine the value.

All ranges disclosed herein are inclusive of the recited endpoint andindependently combinable (for example, the range of “from 2 to 10” isinclusive of the endpoints, 2 and 10, and all the intermediate values).The endpoints of the ranges and any values disclosed herein are notlimited to the precise range or value; they are sufficiently impreciseto include values approximating these ranges and/or values.

As used herein, approximating language may be applied to modify anyquantitative representation that may vary without resulting in a changein the basic function to which it is related. Accordingly, a valuemodified by a term or terms, such as “about” and “substantially,” maynot be limited to the precise value specified, in some cases. In atleast some instances, the approximating language may correspond to theprecision of an instrument for measuring the value. The modifier “about”should also be considered as disclosing the range defined by theabsolute values of the two endpoints. For example, the expression “fromabout 2 to about 4” also discloses the range “from 2 to 4.” The term“about” may refer to plus or minus 10% of the indicated number. Forexample, “about 10%” may indicate a range of 9% to 11%, and “about 1”may mean from 0.9-1.1. Other meanings of “about” may be apparent fromthe context, such as rounding off, so, for example “about 1” may alsomean from 0.5 to 1.4.

In the present disclosure the singular forms “a,” “an,” and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “acompound” is a reference to one or more of such compounds andequivalents thereof known to those skilled in the art, and so forth. Theterm “plurality”, as used herein, means more than one.

The term “subject,” is used herein to refer to an animal, for example ahuman, to whom treatment, including prophylactic treatment, with thepharmaceutical compositions or methods according to the presentinvention, is provided. The term “subject” as used herein refers tohuman and non-human animals.

As used herein, the term “treating” means reducing or eliminating thesigns or symptoms of the condition for which fospropofol is beingadministered.

In some aspects, the disclosure is directed to pharmaceutical dosageforms for oral administration comprising fospropofol or apharmaceutically acceptable salt thereof, a pharmaceutically acceptableacid.

In some embodiments, the pharmaceutical dosage forms of the disclosurecomprise fospropofol:

In other embodiments, the pharmaceutical dosage forms of the disclosurecomprise a pharmaceutically acceptable salt of fospropofol. As usedherein, “pharmaceutically acceptable salt of fospropofol” refers to asalt of fospropofol that is pharmaceutically acceptable and thatpossesses the desired pharmacologic activity. Such salts are generallynon-toxic, and may be inorganic or organic base addition salts.Specifically, such salts include: salts formed when at least one acidicproton present in fospropofol either is replaced by at least one metalion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminumion; or by an organic base such as aliphatic, alicyclic, or aromaticorganic amines, such as ammonia, methylamine, dimethylamine,diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine,ethylenediamine, lysine, arginine, ornithine, choline,N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine, N-methylglucamine piperazine,tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and thelike. Examples of pharmaceutically acceptable salts of fospropofolinclude monosodium, monopotassium, disodium, dipotassium salts,diethylamine, t-butyl amine, ethylene diamine, benzathine, piperazine,ethanolamine, diethanolamine, ammonium, tromethamine, benethamine,histidine, calcium, magnesium, and zinc salts.

In some embodiments, the pharmaceutical dosage forms of the disclosurecomprise fospropofol disodium:

The pharmaceutical dosage forms of the disclosure including apharmaceutically acceptable salt of fospropofol comprise apharmaceutically acceptable acid. Pharmaceutically acceptable acids areknown in the art. Exemplary pharmaceutically acceptable acids includeall applicable stereoisomers including diastereomers, enantiomers andmixtures thereof, for example, 1-hydroxy-2-naphthoic acid,2,2-dichloroacetic acid, 2-hydroxethanesulfonic acid, 4-acetamidobenzoicacid, 4-aminosalicyclic acid, acetic acid, aceturic acid, Acidhydrolyzed proteins, Acid Modified Starch, Aconitic Acid, adipic acid,alginic acid, a-oxo-glutaric acid, benzenesulfonic acid, benzoic acid,butyric acid, camphor-10-sulfonic acid, camphoric acid, capric acid,caproic acid, caprylic acid, carbonic acid, Cholic acid, cinnamic acid,citric acid, cyclamic acid, D(−)-Lactic acid, Desoxycholic acid,D-glucaric acid, D-glucoheptonic acid, D-glucuronic acid,Di(tert-butyl)naphthalenedisulfonic acid,Di(tert-butyl)naphthalenesulfonic acid, DL-lactic acid, DL-mandelicacid, DL-tartaric acid, tartaric acid, dodecylsulfuric acid, Erythorbicacid (D-isoascorbic acid), ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, fumaric acid, galactaric acid, gentisic acid,glutaric acid, glycerophosphoric acid, Glycocholic acid, glycolic acid,hexanedioic acid, hippuric acid, hydrobromic acid, Hydrochloric acid,Iron naphthenate, iron salts, iron salts, isobutyric acid, L(+)-lacticacid, L(+)-potassium acid tartrate, tartaric acid, L(+)-tartaric acid,Lactic acid, lactobionic acid, L-ascorbic acid, ascorbic acid,L-aspartic acid, lauric acid, L-glutamic acid, L-Glutamic acidhydrochloride, Linoleic acid, L-Malic acid, L-pyroglutamic acid,L-tartaric acid, maleic acid, malic acid, malonic acid, methanesulfonicacid, monobasic potassium phosphate, monobasic sodium phosphate,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, naphthenicacids, Niacin (nicotinic acid), nicotinic acid, nitric acid, octanoicacid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,Pectin low acid, Pectinic acid, phosphoric acid, propanoic acid,Propionic acid, p-toluenesulfonic acid, pyruvic acid, saccharin,salicylic acid, sebacic acid, Sodium acid pyrophosphate, Sodium aluminumphosphate, sodium metabisulfite, Sorbic acid, stearic acid, succinicacid, sulfuric acid, tall oil fatty acids, Tannic acid (hydrolyzablegallotannins), Taurocholic acid, thiocyanic acid, Thiodipropionic acid,trifluoroacetic acid, undec-10-enoic acid, orange juice, apple juice,grapefruit juice, as well as combinations thereof. As used herein, a“pharmaceutically acceptable acid” preferably refers to an acid that ison the FDA published inactive ingredient database (IID) for approveddrug products or the generally recognized as safe (GRAS) database foruse in food. In some embodiments, the pharmaceutically acceptable acidis a polyacid such as hyaluronic acid, polyacrylic acid (e.g.,Carbomers), polyaspartic acid, polyglutamic acid or mixtures thereof.

In some embodiments, the pharmaceutically acceptable acid is ascorbicacid, citric acid, malic acid, tartaric acid, succinic acid, fumaricacid, maleic acid, lactic acid, monobasic sodium phosphate, monobasicpotassium phosphate, or sodium metabisulfite.

In other embodiments, the pharmaceutically acceptable acid is ascorbicacid, citric acid, malic acid, or tartaric acid, or all applicablestereoisomers including diastereomers, enantiomers and mixtures thereof.

In some embodiments, the pharmaceutically acceptable acid is ascorbicacid. As used herein, the term “ascorbic acid” refers to DL-ascorbicacid, L-ascorbic acid, D-ascorbic acid, or mixtures thereof. In someembodiments, the ascorbic acid is DL-ascorbic acid. In otherembodiments, the ascorbic acid is L-ascorbic acid. In other embodiments,the ascorbic acid is D-ascorbic acid.

In some embodiments, the pharmaceutically acceptable acid is tartaricacid. As used herein, the term “tartaric acid” refers to DL- tartaricacid, L- tartaric acid, D-tartaric acid, meso-tartaric acid, or mixturesthereof. In some embodiments, the tartaric acid is DL-tartaric acid. Inother embodiments, the tartaric acid is L- tartaric acid. In otherembodiments, the tartaric acid is D- tartaric acid.

In some embodiments, the pharmaceutically acceptable acid is malic acid.As used herein, the term “malic acid” refers to DL- malic acid, L-malicacid, D-malic acid, or mixtures thereof. In some embodiments, the malicacid is DL-malic acid. In other embodiments, the malic acid is L-malicacid. In other embodiments, the malic acid is D-malic acid.

In some embodiments, the pharmaceutically acceptable acid is citricacid.

In some embodiments, the pharmaceutically acceptable acid is fumaricacid, i.e., the trans isomer of butenedioic acid. In some embodiments,the pharmaceutically acceptable acid is maleic acid, i.e., the cisisomer of butenedioic acid. In some embodiments, the pharmaceuticallyacceptable acid is a mixture of the cis isomer of butenedioic acid andthe trans isomer of butenedioic acid. An exemplary compositioncomprising fumaric acid comprises 384.2 mg fospropofol disodium hydrate(equivalent to 300 mg fospropofol disodium), 28.2 mg of polyplasdone XL,2.8 mg of magnesium stearate, and 150.0 mg of fumaric acid. Anotherexemplary composition comprising fumaric acid comprises 127.8 mgfospropofol disodium hydrate (equivalent to 100 mg fospropofoldisodium), 14.7 mg of polyplasdone XL, 1.46 mg of magnesium stearate,and 150.0 mg of fumaric acid.

In some embodiments in which the pharmaceutical dosage forms of thedisclosure comprise fospropofol in acid form, i.e.,

the dosage forms do not include an additional pharmaceuticallyacceptable acid because in such embodiments, the fospropofol acid itselfprovides the acidity to achieve oral bioavailability and/or reducedinter-subject variability.

In some aspects, the pharmaceutical dosage forms of the disclosurefurther comprise a pharmaceutically acceptable excipient. In suchaspects, the pharmaceutically acceptable excipient is present inaddition to the pharmaceutically acceptable acid.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier,diluent, or release modifier to facilitate administration of an agentand that is compatible therewith.

In some embodiments, the pharmaceutically acceptable excipient may bewater, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, starches, sugars, micro-crystalline cellulose,surfactants, polymers, diluents, granulating agents, lubricants,binders, fillers, and disintegrants.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,dicalcium phosphate, hydroxypropyl methyl cellulose, microcrystallinecellulose, and mixtures thereof.

Fillers for use in the pharmaceutical compositions and dosage formsdisclosed herein include, but are not limited to, talc, calciumcarbonate (e.g., granules or powder), microcrystalline cellulose,powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol,starch, dicalcium phosphate, pre-gelatinized starch, and mixturesthereof.

Disintegrants that can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums ormixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof.

In some embodiments, the solid pharmaceutical dosage form is uncoated orcoated to delay disintegration and absorption in the gastrointestinaltract. For example, a time delay material such as glyceryl monostearateor glyceryl distearate can be employed.

Surfactants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, ionic surfactants, andmixtures thereof.

Suitable ionic surfactants include, but are not limited to,alkylammonium salts; fusidic acid salts; fatty acid derivatives of aminoacids, oligopeptides, and polypeptides; glyceride derivatives of aminoacids, oligopeptides, and polypeptides; lecithins and hydrogenatedlecithins; lysolecithins and hydrogenated lysolecithins; phospholipidsand derivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof, lecithins, lysolecithin, phospholipids,lysophospholipids and derivatives thereof; carnitine fatty acid estersalts; salts of alkylsulfates; fatty acid salts; sodium docusate;acylactylates; mono- and di-acetylated tartaric acid esters of mono- anddi-glycerides; succinylated mono- and di-glycerides; citric acid estersof mono- and di-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol,polyglyceryl-10-oleate, Tween 40, Tween 60, sucrose monostearate,sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenolseries, PEG 15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof.

Solubilizers include, but are not limited to, the following: alcoholsand polyols, such as ethanol, isopropanol, butanol, benzyl alcohol,ethylene glycol, propylene glycol, butanediols and isomers thereof,glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethylisosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol,hydroxypropyl methylcellulose and other cellulose derivatives,cyclodextrins and cyclodextrin derivatives; ethers of polyethyleneglycols having an average molecular weight of about 200 to about 6000,such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxyPEG; amides and other nitrogen-containing compounds such as2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide and polyvinylpyrrolidone; esters such as ethylpropionate, tributylcitrate, acetyl triethylcitrate, acetyl tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,triacetin, propylene glycol monoacetate, propylene glycol diacetate,ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof,β-butyrolactone and isomers thereof; and other solubilizers known in theart, such as dimethyl acetamide, dimethyl isosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycol monoethyl ether, andwater.

Release modifiers may include coatings or matrix materials.

Release modifying coatings include but are not limited to polymercoating materials, such as cellulose acetate phthalate, celluloseacetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinylacetate phthalate, ammonio methacrylate copolymers such as those soldunder the Trade Mark Eudragit® RS and RL, poly acrylic acid and polyacrylate and methacrylate copolymers such as those sold under the TradeMark Eudragite S and L, polyvinyl acetaldiethylamino acetate,hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels andgel-forming materials, such as carboxyvinyl polymers, sodium alginate,sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin,starch, and cellulose based cross-linked polymers—in which the degree ofcrosslinking is low so as to facilitate adsorption of water andexpansion of the polymer matrix, hydoxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer(Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gumarabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers)poly(hydroxyalkyl methacrylate) (m. wt. ^(˜)5 k-5,000 k),polyvinylpyrrolidone (m. wt. ^(˜)10 k-360 k), anionic and cationichydrogels, polyvinyl alcohol having a low acetate residual, a swellablemixture of agar and carboxymethyl cellulose, copolymers of maleicanhydride and styrene, ethylene, propylene or isobutylene, pectin (m.wt. ^(˜)30 k-300 k), polysaccharides such as agar, acacia, karaya,tragacanth, algins and guar, polyacrylamides, Polyox® polyethyleneoxides (m. wt. ^(˜)100 k-5,000 k), AquaKeep® acrylate polymers, diestersof polyglucan, crosslinked polyvinyl alcohol and polyN-vinyl-2-pyrrolidone, sodium starch glucolate (e.g. Explotab®; EdwardMandell C. Ltd.); hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, polyethyleneoxides (e.g. Polyox®, Union Carbide), methyl ethyl cellulose,ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan,polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerolfatty acid esters, polyacrylamide, polyacrylic acid, copolymers ofmethacrylic acid or methacrylic acid (e.g. Eudragit®, Rohm and Haas),other acrylic acid derivatives, sorbitan esters, natural gums,lecithins, pectin, alginates, ammonia alginate, sodium, calcium,potassium alginates, propylene glycol alginate, agar, and gums such asarabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan,scleroglucan and mixtures and blends thereof. As will be appreciated bythe person skilled in the art, excipients such as plasticisers,lubricants, solvents and the like may be added to the coating. Suitableplasticisers include for example acetylated monoglycerides; butylphthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethylphthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol;triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetylmonoglyceride; polyethylene glycols; castor oil; triethyl citrate;polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate,acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctylazelate, epoxidised tallate, triisoctyl trimellitate, diethylhexylphthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decylphthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate,tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexylsebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

Release-modifying matrix materials include hydrophilic polymers,hydrophobic polymers and mixtures thereof, dicalcium phosphate,microcrytalline cellulose, sodium carboxymethylcellulose,hydoxyalkylcelluloses such as hydroxypropylmethylcellulose andhydroxypropylcellulose, polyethylene oxide, alkylcelluloses such asmethylcellulose and ethylcellulose, polyethylene glycol,polyvinylpyrrolidone, cellulose actetate, cellulose acetate butyrate,cellulose actetate phthalate, cellulose acteate trimellitate,polyvinylacetate phthalate, polyalkylmethacrylates, polyvinyl acetate,Poly(2-hydroxy ethyl methacrylate), Poly(N-vinyl pyrrolidone),Poly(methyl methacrylate), Poly(vinyl alcohol), Poly(acrylic acid),Polyacrylamide, Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol),Poly(methacrylic acid), Polylactides (PLA), Polyglycolides (PGA),Poly(lactide-co-glycolides) (PLGA), Polyanhydrides, and Polyorthoesters,and mixture thereof.

In some embodiments, the fospropofol (or pharmaceutically acceptablesalt thereof) and the pharmaceutically acceptable acid can be present inthe same unit dosage form. In other embodiments, all or a portion of thepharmaceutically acceptable acid can be administered separately from theunit dosage form comprising the fospropofol (or pharmaceuticallyacceptable salt thereof).

In some aspects, the pharmaceutical dosage forms of the disclosure arethose that when dissolved in water, contain an amount ofpharmaceutically acceptable acid necessary to drive the ionicequilibrium of the aqueous solution towards a pH lower than 7 andpreferably ≤4.5.

In some aspects, the pharmaceutical dosage forms of the disclosure arethose wherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 6.3, such as, for example,a pH of less than or equal to 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6,5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2,4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8,2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4,1.3, 1.2, 1.1, or 1.0.

The term “therapeutically effective amount”, as used herein, refers toan amount sufficient to reduce or eliminate the signs or symptoms of thecondition for which fospropofol is being administered. Thetherapeutically effective amount may be contained in a single dosageform, or may be the cumulative amount contained in multiple dosageforms.

In some embodiments, a therapeutically effective amount of fospropofol,or a pharmaceutically acceptable salt of fospropofol, is 10-4800 mg (ona fospropofol basis), for example, an amount that is about (i.e., thespecified number ±10%) any one of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60mg, 70 mg, 80 mg, 0 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg,850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg,1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg,1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg,2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg,2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg,2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg, 3100 mg, 3150 mg, 3200 mg,3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg,3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg,4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg,4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, or 4800mg.

In other embodiments, a therapeutically effective amount of fospropofol,or a pharmaceutically acceptable salt of fospropofol, is about 1 mg/kgto about 80 mg/kg (on a fospropofol basis), for example, an amount thatis about (i.e., the specified number ±10%) any one of 1 mg/kg, 2 mg/kg,3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg,11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32mg/kg, 33 mg/kg, 34 mg/kg, 35 mg/kg, 36 mg/kg, 37 mg/kg, 38 mg/kg, 39mg/kg, 40 mg/kg, 41 mg/kg, 42 mg/kg, 43 mg/kg, 44 mg/kg, 45 mg/kg, 46mg/kg, 47 mg/kg, 48 mg/kg, 49 mg/kg, 50 mg/kg, 51 mg/kg, 52 mg/kg, 53mg/kg, 54 mg/kg, 55 mg/kg, 56 mg/kg, 57 mg/kg, 58 mg/kg, 59 mg/kg, 60mg/kg, 61 mg/kg, 62 mg/kg, 63 mg/kg, 64 mg/kg, 65 mg/kg, 66 mg/kg, 67mg/kg, 68 mg/kg, 69 mg/kg, 70 mg/kg, 71 mg/kg, 72 mg/kg, 73 mg/kg, 74mg/kg, 75 mg/kg, 76 mg/kg, 77 mg/kg, 78 mg/kg, 79 mg/kg, or 80 mg/kg.

In some embodiments, the pharmaceutical dosage forms of the disclosureare those wherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 4.5.

In other embodiments, the pharmaceutical dosage forms of the disclosureare those wherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 4.2.

In other embodiments, the pharmaceutical dosage forms of the disclosureare those wherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 4.0.

In some aspects, the pharmaceutical dosage forms of the disclosure arethose releasing the active ingredient (e.g., the fospropofol or thefospropofol salt) immediately or in modified or extended-release manner.

In some aspects, the pharmaceutical dosage forms of the disclosure arethose wherein dissolution of an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HC1 at 37° C., results in atleast 30% (e.g., 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, 98%, or 99% or greater than 99%) of the fospropofol orpharmaceutically acceptable salt thereof (on a fospropofol basis) in thedosage form being released from the dosage form within 60 minutes orless (e.g., within 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10minutes, or within 5 minutes.

In some embodiments, the pharmaceutical dosage forms of the disclosureare those wherein dissolution of an amount of the dosage form containinga therapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HC1 at 37° C. results in atleast 30% of the fospropofol or pharmaceutically acceptable salt thereof(on a fospropofol basis) in the dosage form being released from thedosage form within 30 minutes.

In some embodiments, the pharmaceutical dosage forms of the disclosureare those wherein dissolution of an amount of the dosage form containinga therapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HC1 at 37° C. results in atleast 50% of the fospropofol or pharmaceutically acceptable salt thereof(on a fospropofol basis) in the dosage form being released from thedosage form within 60 minutes.

In other embodiments, the pharmaceutical dosage forms of the disclosureare those wherein dissolution of an amount of the dosage form containinga therapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HC1 at 37° C. results in atleast 90% of the fospropofol or pharmaceutically acceptable salt thereof(on a fospropofol basis) in the dosage form being released from thedosage form within 30 minutes.

In some aspects, the pharmaceutical dosage forms of the disclosure arethose wherein the mole ratio of fospropofol, or a pharmaceuticallyacceptable salt thereof, to pharmaceutically acceptable acid is 3:1 orless, such as, for example, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1,0.5:1, 0.55:1, 0.6:1, 0.65:1, 0.7:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1,0.95:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1,1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1,2.9:1, or 3:1.

The pharmaceutical dosage forms of the disclosure may be tablets,capsules, caplets, softgels, sterile aqueous or organic solutions,reconstitutable powders, elixirs, liquids, colloidal or other types ofsuspensions, emulsions, beads, beadlets, granules, microparticles,nanoparticles, and combinations thereof.

In some embodiments, the pharmaceutical dosage form of the disclosure isa tablet, capsule, or softgel.

In some aspects, the disclosure is directed to methods of administeringfospropofol or a pharmaceutically acceptable salt thereof to a subjectin need thereof, the method comprising orally administering fospropofol,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable acid, to the subject.

In some embodiments, the disclosure is directed to methods ofadministering fospropofol or a pharmaceutically acceptable salt thereofto a subject in need thereof, comprising orally administering to thesubject a pharmaceutical dosage form of this disclosure.

In other embodiments of the disclosed methods, the subject is orallyco-administered fospropofol (or a pharmaceutically acceptable saltthereof) and a pharmaceutically acceptable acid.

As used herein, the term “orally co-administering” refers tosimultaneous administration, or sequential administration in such amanner that the fospropofol, or a pharmaceutically acceptable saltthereof, and the pharmaceutically acceptable acid are present in thesubject's stomach at the same time.

In some embodiments of the disclosed methods, the fospropofol (orpharmaceutically acceptable salt thereof) and the pharmaceuticallyacceptable acid are administered in the same unit dosage form (i.e., thefospropofol or pharmaceutically acceptable salt thereof are present inthe same dosage form together with the pharmaceutically acceptableacid).

In other embodiments, all or a portion of the pharmaceuticallyacceptable acid is administered separately from the dosage formcomprising the fospropofol (or pharmaceutically acceptable saltthereof).

In some embodiments, the methods are for orally administeringfospropofol.

In other embodiments, the methods are for orally administering apharmaceutically acceptable salt of fospropofol.

In other embodiments, the methods are for orally administeringfospropofol disodium.

In some embodiments of the disclosed methods, the pharmaceuticallyacceptable acid used in the methods of the disclosure is1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxethanesulfonic acid, 4-acetamidobenzoic acid, 4-aminosalicyclicacid, acetic acid, aceturic acid, Acid hydrolyzed proteins, AcidModified Starch, Aconitic Acid, adipic acid, alginic acid,a-oxo-glutaric acid, benzenesulfonic acid, benzoic acid, butyric acid,camphor-10-sulfonic acid, camphoric acid, capric acid, caproic acid,caprylic acid, carbonic acid, Cholic acid, cinnamic acid, citric acid,cyclamic acid, D(−)-Lactic acid, Desoxycholic acid, D-glucaric acid,D-glucoheptonic acid, D-glucuronic acid,Di(tert-butyl)naphthalenedisulfonic acid,Di(tert-butyl)naphthalenesulfonic acid, DL-lactic acid, DL-mandelicacid, DL-tartaric acid, tartaric acid, dodecylsulfuric acid, Erythorbicacid (D-isoascorbic acid), ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, fumaric acid, galactaric acid, gentisic acid,glutaric acid, glycerophosphoric acid, Glycocholic acid, glycolic acid,hexanedioic acid, hippuric acid, hydrobromic acid, Hydrochloric acid,Iron naphthenate, iron salts, iron salts, isobutyric acid, L(+)-lacticacid, L(+)-potassium acid tartrate, L(+)-tartaric acid, Lactic acid,lactobionic acid, L-ascorbic acid, ascorbic acid, L-aspartic acid,lauric acid, L-glutamic acid, L-Glutamic acid hydrochloride, Linoleicacid, L-Malic acid, L-pyroglutamic acid, L-tartaric acid, maleic acid,malic acid, malonic acid, methanesulfonic acid, monobasic potassiumphosphate, monobasic sodium phosphate, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, naphthenic acids, Niacin (nicotinic acid),nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid,oxalic acid, palmitic acid, pamoic acid, Pectin low acid, Pectinic acid,phosphoric acid, propanoic acid, Propionic acid, p-toluenesulfonic acid,pyruvic acid, saccharin, salicylic acid, sebacic acid, Sodium acidpyrophosphate, Sodium aluminum phosphate, sodium metabisulfite, Sorbicacid, stearic acid, succinic acid, sulfuric acid, tall oil fatty acids,Tannic acid (hydrolyzable gallotannins), Taurocholic acid, thiocyanicacid, Thiodipropionic acid, trifluoroacetic acid, undec-10-enoic acid,orange juice, apple juice, grapefruit juice, or a combination thereof.

In some embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is ascorbic acid. In some embodiments, theascorbic acid is DL-ascorbic acid. In other embodiments, the ascorbicacid is L-ascorbic acid. In other embodiments, the ascorbic acid isD-ascorbic acid.

In other embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is tartaric acid. In some embodiments, thetartaric acid is DL-tartaric acid. In other embodiments, the tartaricacid is L-tartaric acid. In other embodiments, the tartaric acid isD-tartaric acid.

In some embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is citric acid.

In some embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is malic acid. In some embodiments, the malicacid is DL-malic acid. In other embodiments, the malic acid is L-malicacid. In other embodiments, the malic acid is D-malic acid.

In some methods of the disclosure, the administration of fospropofol (ora pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in a propofol Cmax that is greater than the Cmaxresulting from administering fospropofol, or a pharmaceuticallyacceptable salt thereof, without co-administration of thepharmaceutically acceptable acid. The term “Cmax”, as used herein,refers to the peak concentration of propofol observed in the subject'splasma following administration of fospropofol or a pharmaceuticallyacceptable salt thereof. The concentration of propofol in the subject'splasma samples can be determined using standard analytical methods. Insome embodiments of such methods, the administration of fospropofol (ora pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid comprises administering a pharmaceutical dosage form asdescribed herein.

In some embodiments of the methods of the disclosure, the administrationof fospropofol (or a pharmaceutically acceptable salt thereof) and apharmaceutically acceptable acid results in a propofol Cmax that is atleast 1.2 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid,such as for example, at least 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 times greater.

In some embodiments of the methods of the disclosure, the propofol Cmaxis 1.2 times greater than a propofol Cmax resulting from administeringfospropofol, or a pharmaceutically acceptable salt thereof withoutadministration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis at least 1.5 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis at least 2 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis at least 2.5 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis 3 times greater than a propofol Cmax resulting from administeringfospropofol, or a pharmaceutically acceptable salt thereof, withoutadministration of the pharmaceutically acceptable acid.

In some methods of the disclosure, the administration of fospropofol (ora pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in a propofol AUC that is greater than apropofol AUC resulting from administering fospropofol, or apharmaceutically acceptable salt thereof, without administration of thepharmaceutically acceptable acid. In some embodiments, the AUC isAUC_(t). The term “AUC_(t)”, as used herein, refers to the area underthe plasma propofol concentration-time curve from time zero to time t.In other embodiments, the AUC is AUC_(∞). The term “AUC_(∞)”, as usedherein, refers to the AUC obtained by extrapolation of AUC₀, to ∞. Insome embodiments of such methods, the administration of fospropofol (ora pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid comprises administering a pharmaceutical dosage form asdescribed herein.

In some embodiments of the methods of the disclosure, the propofolAUC_(∞) is at least 1.5 times greater than a propofol AUC_(∞) resultingfrom administering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid,such as for example, at least 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, or 4 times greater.

In some embodiments of the methods of the disclosure, the propofolAUC_(∞) is 1.5 times greater than a propofol AUC_(∞) resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofolAUC_(∞) is at least 1.6 times greater than a propofol AUC_(∞) resultingfrom administering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofolAUC_(∞) is at least 2 times greater than a propofol AUC_(∞) resultingfrom administering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofolAUC_(∞) is at least 2.5 times greater than a propofol AUC_(∞) resultingfrom administering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofolAUC_(∞) is at least 3 times greater than a propofol AUC_(∞) resultingfrom administering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some aspects, the methods of the disclosure result in plasmaconcentrations of fospropofol or propofol that exhibit a food effect.The term “food effect,” as used herein, means that the extent and/orrate of drug absorption depends on whether the subject is fed or fastedat the time that the drug is administered.

The term “fed” as used herein, means that the subject has eaten foodwithin one hour of less of ingesting the fospropofol or apharmaceutically acceptable salt thereof. For example, following anovernight fast of at least 10 hours, the subject starts a meal 30minutes before administration of the drug product, and eats the mealwithin 30 minutes or less. The fospropofol or a pharmaceuticallyacceptable salt thereof is taken with 240 mL (8 fl. oz.) of water.Additional water is allowed ad lib except for 1 hour before and 1 hourafter drug administration. No food is allowed for at least 4 hours afterthe dose.

In the context of a food effect study, fasted conditions may be asfollows: Following an overnight fast of at least 10 hours, investigatorsshould administer the drug product to study subjects with 240 mL (i.e.,8 fluid ounces) of water. Additional water is permitted ad lib exceptfor the period 1 hour before to 1 hour after administration of the drugproduct. The study subjects should not consume food for at least 4 hoursafter the dose. Subjects should receive standardized meals scheduled atthe same time throughout the study.

The term “fasted” as used herein, means that the subject has not eatenfood within one hour of less of ingesting the fospropofol or apharmaceutically acceptable salt thereof. For example, following anovernight fast of at least 10 hours, fospropofol or a pharmaceuticallyacceptable salt thereof is administered with 240 mL (i.e., 8 fluidounces) of water. Additional water is permitted ad lib except for theperiod 1 hour before to 1 hour after administration of the drug product.the subject does not consume food for at least 4 hours after the dose.

In the context of a food effect study, fed conditions may be as follows:Following an overnight fast of at least 10 hours, the study should startthe recommended meal 30 minutes before administration of the drugproduct. Trial subjects should eat this meal in 30 minutes or less. thestudy subjects should take the drug product with 240 mL (8 fl. oz.) ofwater. Additional water is allowed ad lib except for 1 hour before and 1hour after drug administration. No food is allowed for at least 4 hoursafter the dose.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is about 0.3—1.5, for example, about 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is 0.3 or greater, such as, for example, 0.3, 0.35, 0.4,0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05,1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is 0.3 or greater, such as, for example, 0.3 or greater, 0.35or greater, 0.4 or greater, 0.45 or greater, 0.5 or greater, 0.55 orgreater, 0.6 or greater, 0.65 or greater, 0.7 or greater, 0.75 orgreater, 0.8 or greater, 0.85 or greater, 0.9 or greater, 0.95 orgreater, 1.0 or greater, 1.05 or greater, 1.1 or greater, 1.15 orgreater, 1.2 or greater, 1.25 or greater, 1.3 or greater, 1.35 orgreater, 1.4 or greater, 1.45 or greater, 1.5 or greater, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed) that is atleast 30% of the corresponding plasma fospropofol Cmax (fasted) such as,for example, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%,150%, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed) that is atleast 30% of the corresponding plasma fospropofol Cmax (fasted) such as,for example, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 100%, at least 105%, at least 110%, at least 115%, at least 120%,at least 125%, at least 130%, at least 135%, at least 140%, at least145%, at least 150%, and the like.

As used herein, the term “Cmax (fasted)”, refers to the peakconcentration in the plasma a following administration of fospropofol ora pharmaceutically acceptable salt thereof to a subject that is fasted.As used herein, the term “Cmax (fed)”, refers to the peak concentrationin the plasma following administration of fospropofol or apharmaceutically acceptable salt thereof to a subject that is fed. Thepeak concentration of fopropofol in the subject's plasma samples can bedetermined using an appropriate pharmacokinetic model applied to aplasma concentration vs. time profile determined using standardanalytical methods. Appropriate pharmacokinetic models for determiningCmax are known to those of ordinary skill in the art.

In some embodiments of the disclosed methods, the Cmax (fed):Cmax(fasted) ratio is calculated using the arithmetic mean of the individualCmax (fed) values calculated in a population of subjects and thearithmetic mean of the individual Cmax (fasted) values calculated in apopulation of subjects.

In some embodiments, administration of compositions of the disclosureresults in plasma fospropofol Cmax (fed):Cmax (fasted) ratio that isabout 0.3-1.5, for example, about 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1.0, 1.1, 1.2, 1.3, 1.4, or 1.5.

In some embodiments, administration of compositions of the disclosureresults in plasma fospropofol Cmax (fed):Cmax (fasted) ratio that is 0.3or greater, such as, for example, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, 1.25,1.3, 1.35, 1.4, 1.45, 1.5, and the like.

In some embodiments, administration of compositions of the disclosureresults in plasma fospropofol Cmax (fed):Cmax (fasted) ratio that is 0.3or greater, such as, for example, 0.3 or greater, 0.35 or greater, 0.4or greater, 0.45 or greater, 0.5 or greater, 0.55 or greater, 0.6 orgreater, 0.65 or greater, 0.7 or greater, 0.75 or greater, 0.8 orgreater, 0.85 or greater, 0.9 or greater, 0.95 or greater, 1.0 orgreater, 1.05 or greater, 1.1 or greater, 1.15 or greater, 1.2 orgreater, 1.25 or greater, 1.3 or greater, 1.35 or greater, 1.4 orgreater, 1.45 or greater, 1.5 or greater, and the like.

In some embodiments, administration of compositions of the disclosureresults in plasma fospropofol Cmax (fed) that is at least 30% of thecorresponding plasma fospropofol Cmax (fasted) such as, for example,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, andthe like.

In some embodiments, administration of compositions of the disclosureresults in plasma fospropofol Cmax (fed) that is at least 30% of thecorresponding plasma fospropofol Cmax (fasted) such as, for example, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, at least 100%, atleast 105%, at least 110%, at least 115%, at least 120%, at least 125%,at least 130%, at least 135%, at least 140%, at least 145%, at least150%, and the like.

In some embodiments of the methods of the disclosure, the ratio of theplasma fospropofol Cmax (fed):Cmax (fasted) resulting fromadministration of fospropofol (or a pharmaceutically acceptable saltthereof) and a pharmaceutically acceptable acid is greater than theratio of plasma fospropofol Cmax (fed):Cmax (fasted) resulting fromadministration of fospropofol (or a pharmaceutically acceptable saltthereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 1.25 times greater, at least 1.5 timesgreater, at least 2 times greater, at least 2.5 times greater, at least3 times greater, at least 3.5 times greater, at least 4 times greater,at least 4.5 times greater, at least 5 times greater, at least 5.5 timesgreater, at least 6 times greater, at least 6.5 times greater, at least7 times greater, at least 7.5 times greater, at least 8 times greater,at least 8.5 times greater, at least 9 times greater, at least 9.5 timesgreater, or at least 10 times greater than the ratio of plasmafospropofol Cmax (fed):Cmax (fasted) resulting from administration offospropofol (or a pharmaceutically acceptable salt thereof) without thepharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 5 times greater or at least 6 times greaterthan the ratio of plasma fospropofol Cmax (fed):Cmax (fasted) resultingfrom administration of a fospropofol (or a pharmaceutically acceptablesalt thereof) composition without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid is atleast 125%, at least 150%, at least 200%, at least 250%, at least 300%,at least 350%, at least 400%, or at least 450%, at least 500%, at least550%, at least 600%, at least 650%, at least 700%, at least 750%, atleast 800%, at least 850%, at least 900%, at least 950%, or at least1000%, of the ratio of plasma fospropofol Cmax (fed):Cmax (fasted)resulting from administering a fospropofol (or a pharmaceuticallyacceptable salt thereof) composition without a pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of the compositions of thedisclosure is at least 1.25 times greater, at least 1.5 times greater,at least 2 times greater, at least 2.5 times greater, at least 3 timesgreater, at least 3.5 times greater, at least 4 times greater, at least4.5 times greater, at least 5 times greater, at least 5.5 times greater,at least 6 times greater, at least 6.5 times greater, at least 7 timesgreater, at least 7.5 times greater, at least 8 times greater, at least8.5 times greater, at least 9 times greater, at least 9.5 times greater,or at least 10 times greater than the ratio of plasma fospropofol Cmax(fed):Cmax (fasted) resulting from administration of a fospropofol (or apharmaceutically acceptable salt thereof) composition without thepharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of the compositions of thedisclosure at least 5 times greater or at least 6 times greater than theratio of plasma fospropofol Cmax (fed):Cmax (fasted) resulting fromadministration of a fospropofol (or a pharmaceutically acceptable saltthereof) composition without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of the compositions of thedisclosure is at least 125%, at least 150%, at least 200%, at least250%, at least 300%, at least 350%, at least 400%, or at least 450%, atleast 500%, at least 550%, at least 600%, at least 650%, at least 700%,at least 750%, at least 800%, at least 850%, at least 900%, at least950%, or at least 1000%, of the ratio of plasma fospropofol Cmax(fed):Cmax (fasted) resulting from administering a fospropofol (or apharmaceutically acceptable salt thereof) composition without apharmaceutically acceptable acid.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio that is about0.4 to 1.0, for example about 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7,0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio that is 0.4or greater, such as, for example, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7,0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, and the like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio that is 0.4or greater, such as, for example, 0.4 or greater, 0.45 or greater, 0.5or greater, 0.55 or greater, 0.6 or greater, 0.65 or greater, 0.7 orgreater, 0.75 or greater, 0.8 or greater, 0.85 or greater, 0.9 orgreater, 0.95 or greater, 1.0 or greater, 1.05 or greater, 1.10 orgreater, 1.15 or greater, 1.20 or greater, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol

AUC_(∞) (fed) that is at least 40% of the corresponding plasmafospropofol AUC_(∞) (fasted) such as, for example, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%,125%, 130%, 135%, 140%, 145%, 150%, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol AUC_(∞) (fed) that is atleast 40% of the corresponding plasma fospropofol AUC_(∞) (fasted) suchas, for example, at least 40%, at least 45%, at least 50%, at least 55%,at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 100%, at least 105%, atleast 110%, at least 115%, at least 120%, at least 125%, at least 130%,at least 135%, at least 140%, at least 145%, at least 150%, and thelike.

As used herein, the term “AUC_(∞) (fasted)”, refers to the area underthe plasma concentration-time curve from extrapolation of AUC₀ to ∞following administration of fospropofol or a pharmaceutically acceptablesalt thereof to a subject that is fasted. As used herein, the term“AUC_(∞) (fed)”, refers to the area under the plasma concentration-timecurve from extrapolation of AUC₀ to ∞ following administration offospropofol or a pharmaceutically acceptable salt thereof to a subjectthat is fed. Methods for determining concentration-time curves and AUCare known to those of ordinary skill in the art.

In some embodiments of the disclosed methods, the AUC_(∞) (fed) :AUC_(∞) (fasted) ratio is calculated using the arithmetic mean of theindividual AUC_(∞) (fed) values calculated in a population of subjectsand the arithmetic mean of the individual AUC_(∞) (fasted) valuescalculated in a population of subjects.

In some embodiments, administering the compositions of the disclosureresults in plasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio thatis about 0.4 to 1.0, for example about 0.4, 0.45, 0.5, 0.55, 0.6, 0.65,0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering the compositions of the disclosureresults in plasma fospropofol AUC_(∞) (fasted):AUC_(∞) (fed) ratio thatis 0.4 or greater, such as, for example, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, andthe like.

In some embodiments, administering the compositions of the disclosureresults in plasma fospropofol AUC_(∞) (fasted):AUC_(∞) (fed) ratio thatis 0.4 or greater, such as, for example, 0.4 or greater, 0.45 orgreater, 0.5 or greater, 0.55 or greater, 0.6 or greater, 0.65 orgreater, 0.7 or greater, 0.75 or greater, 0.8 or greater, 0.85 orgreater, 0.9 or greater, 0.95 or greater, 1.0 or greater, 1.05 orgreater, 1.10 or greater, 1.15 or greater, 1.20 or greater, and thelike.

In some embodiments, administering the compositions of the disclosureresults in plasma fospropofol AUC_(∞) (fed) that is at least 40% of thecorresponding plasma fospropofol AUC_(∞) (fasted) such as, for example,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%,110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, and the like.

In some embodiments, administering the compositions of the disclosureresults in plasma fospropofol AUC_(∞) (fed) that is at least 40% of thecorresponding plasma fospropofol AUC_(∞) (fasted) such as, for example,at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, at least 100%, at least 105%, at least 110%, atleast 115%, at least 120%, at least 125%, at least 130%, at least 135%,at least 140%, at least 145%, at least 150%, and the like.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is greater than the ratio of plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) without the pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 1.5 time greater, at least 2 times greater,at least 2.5 times greater, at least 3 times greater, at least 3.5 timesgreater, at least 4 times greater, or at least 4.5 times greater thanthe ratio of plasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) resultingfrom administering fospropofol (or a pharmaceutically acceptable saltthereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 2 times greater or at least 2.5 timesgreater than the ratio of plasma fospropofol AUC_(∞) (fed):AUC_(∞)(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 150%, at least 200%, at least 250%, at least300%, at least 350%, at least 400%, or at least 450% of the ratio ofplasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) resulting fromadministering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is greater than the ratio of plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering a fospropofol (or apharmaceutically acceptable salt thereof) composition without apharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is at least 1.5 time greater, at least 2 times greater,at least 2.5 times greater, at least 3 times greater, at least 3.5 timesgreater, at least 4 times greater, or at least 4.5 times greater thanthe ratio of plasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) resultingfrom administering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is at least 2 times greater or at least 2.5 times greaterthan the ratio of plasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted)resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) composition without a pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is at least 150%, at least 200%, at least 250%, at least300%, at least 350%, at least 400%, or at least 450% of the ratio ofplasma fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) resulting fromadministering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio thatis about 0.4 to 1.0, for example about 0.4, 0.45, 0.5, 0.55, 0.6, 0.65,0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio thatis 0.4 or greater, such as, for example, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, andthe like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio thatis 0.4 or greater, such as, for example, 0.4 or greater, 0.45 orgreater, 0.5 or greater, 0.55 or greater, 0.6 or greater, 0.65 orgreater, 0.7 or greater, 0.75 or greater, 0.8 or greater, 0.85 orgreater, 0.9 or greater, 0.95 or greater, 1.0 or greater, 1.05 orgreater, 1.10 or greater, 1.15 or greater, 1.20 or greater, and thelike.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma total fospropofol AUC_(∞) (fed) thatis at least 40% of the corresponding plasma total fospropofol AUC_(∞)(fasted) such as, for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%,140%, 145%, 150%, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma total fospropofol AUC_(∞) (fed) thatis at least 40% of the corresponding plasma total fospropofol AUC_(∞)(fasted) such as, for example, at least 40%, at least 45%, at least 50%,at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, at least 100%, atleast 105%, at least 110%, at least 115%, at least 120%, at least 125%,at least 130%, at least 135%, at least 140%, at least 145%, at least150%, and the like.

As used here, the term “plasma total fospropofol AUC_(∞) (fasted)”,refers to the sum of the AUC_(∞) (fasted) for fospropofol and theAUC_(∞) (fasted) for propofol, following administration of fospropofolor a pharmaceutically acceptable salt thereof to a subject that isfasted. As used here, the term “plasma total fospropofol AUC_(∞) (fed)”,refers to the sum of the AUC_(∞) (fed) for fospropofol and the AUC_(∞)(fed) for propofol, following administration of fospropofol or apharmaceutically acceptable salt thereof to a subject that is fed.Methods for determining concentration-time curves and AUC are known tothose of ordinary skill in the art.

In some embodiments of the disclosed methods, the plasma totalfospropofol AUC_(∞) (fed):AUC_(∞) (fasted) ratio is calculated using thearithmetic mean of the individual AUC_(∞) (fed) values calculated in apopulation of subjects and the arithmetic mean of the individual AUC_(∞)(fasted) values calculated in a population of subjects.

In some embodiments, administering the compositions of the disclosureresults in plasma total fospropofol AUC_(∞) (fasted):AUC_(∞) (fed) ratiothat is about 0.4 to 1.0, for example about 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering the compositions of the disclosureresults in plasma total fospropofol AUC_(∞) (fasted):AUC_(∞) (fed) ratiothat is 0.4 or greater, such as, for example, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, andthe like.

In some embodiments, administering the compositions of the disclosureresults in plasma total fospropofol AUC_(∞) (fasted):AUC_(∞) (fed) ratiothat is 0.4 or greater, such as, for example, 0.4 or greater, 0.45 orgreater, 0.5 or greater, 0.55 or greater, 0.6 or greater, 0.65 orgreater, 0.7 or greater, 0.75 or greater, 0.8 or greater, 0.85 orgreater, 0.9 or greater, 0.95 or greater, 1.0 or greater, 1.05 orgreater, 1.10 or greater, 1.15 or greater, 1.20 or greater, and thelike.

In some embodiments, administering the compositions of the disclosureresults in plasma total fospropofol AUC_(∞) (fed) that is at least 40%of the corresponding plasma total fospropofol AUC_(∞) (fasted) such as,for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, andthe like.

In some embodiments, administering the compositions of the disclosureresults in plasma total fospropofol AUC_(∞) (fed) that is at least 40%of the corresponding plasma total fospropofol AUC_(∞) (fasted) such as,for example, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 100%, at least 105%, atleast 110%, at least 115%, at least 120%, at least 125%, at least 130%,at least 135%, at least 140%, at least 145%, at least 150%, and thelike.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is greater than the ratio of plasma total fospropofolAUC_(∞) (fed):AUC_(∞) (fasted) resulting from administering fospropofol(or a pharmaceutically acceptable salt thereof) without thepharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 1.5 time greater, at least 2 times greater,at least 2.5 times greater, at least 3 times greater, at least 3.5 timesgreater, at least 4 times greater, or at least 4.5 times greater thanthe ratio of plasma total fospropofol AUC_(∞) (fed):AUC_(∞) (fasted)resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 2 times greater or at least 2.5 timesgreater than the ratio of plasma total fospropofol AUC_(∞) (fed):AUC_(∞)(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 150%, at least 200%, at least 250%, at least300%, at least 350%, at least 400%, or at least 450% of the ratio ofplasma total fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) resulting fromadministering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is greater than the ratio of plasma total fospropofolAUC_(∞) (fed):AUC_(∞) (fasted) resulting from administering afospropofol (or a pharmaceutically acceptable salt thereof) compositionwithout a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is at least 1.5 time greater, at least 2 times greater,at least 2.5 times greater, at least 3 times greater, at least 3.5 timesgreater, at least 4 times greater, or at least 4.5 times greater thanthe ratio of plasma total fospropofol AUC_(∞) (fed):AUC_(∞) (fasted)resulting from administering a fospropofol (or a pharmaceuticallyacceptable salt thereof) composition without a pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is at least 2 times greater or at least 2.5 times greaterthan the ratio of plasma total fospropofol AUC_(∞) (fed):AUC_(∞)(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) composition without a pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC_(∞) (fasted) resulting from administering the compositions ofthe disclosure is at least 150%, at least 200%, at least 250%, at least300%, at least 350%, at least 400%, or at least 450% of the ratio ofplasma total fospropofol AUC_(∞) (fed):AUC_(∞) (fasted) resulting fromadministering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments of the methods disclosed herein, the subject is ahuman.

In some embodiments of the methods disclosed herein, the subject isexperiencing hypochlorhydria or achlorhydria prior to the administrationof a dosage form as described herein. In some embodiments, the subjectis diagnosed with hypochlorhydria or achlorhydria prior to theadministration. In other embodiments of the methods disclosed herein,the subject is suspected of having hypochlorhydria or achlorhydria priorto the administration.

In some embodiments of the methods disclosed herein, the subject hasbeen administered a proton pump inhibitor (PPI) prior to theadministration of a dosage form as described herein. Exemplary protonpump inhibitors include Omeprazole (Prilosec), Esomeprazole (Nexium),Lansoprazole (Prevacid), Rabeprazole (AcipHex), Pantoprazole (Protonix),Dexlansoprazole (Dexilant), and Zegerid (omeprazole with sodiumbicarbonate).

In some aspects, the methods described herein are directed to treating adisease or disorder in a subject in need thereof.

In some embodiments, the methods described herein are directed totreating a disease or disorder comprising orally administering to asubject a pharmaceutical dosage form described herein.

In other embodiments, the methods described herein are directed totreating a disease or disorder comprising orally administeringfospropofol, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable acid, to a subject.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is migraine, acute repetitiveseizures, seizure clusters, neuropathic pain, postherpetic neuralgia,traumatic brain injury, Alzheimer's disease, epilepsy, anxiety, fragileX syndrome, post-traumatic stress disorder, lysosomal storage disorders(Niemann-Pick type C disease), depression (including post-partumdepression), premenstrual dysphoric disorder, alcohol craving, orsmoking cessation.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is migraine. The term “migraine,” asused herein, refers to a chronic neurovascular disorder characterized byrecurrent attacks of often severe headache (“migraine attacks”),typically accompanied by nausea and sensitivity to light and/or sound.Migraine is a clinical diagnosis, criteria for which would be known andunderstood by those practicing in the treatment of migraine, and wouldinclude, for example, the criteria proposed by the InternationalHeadache Society (IHS). See http://ihs-classification.org/en/.

In some embodiments, the subject's migraine is migraine with aura.Migraine with aura (also referred to as classic migraine) ischaracterized by focal neurological symptoms that typically precede, orsometimes accompany, the headache.

In other embodiments, the subject's migraine is migraine without aura.Migarine without aura (also referred to as common migraine) ischaracterized by the absence of focal neurological symptoms thattypically precede, or sometimes accompany, the headache.

In other embodiments, the subject's migraine is cluster headache.

In other embodiments, the subject's migraine is intractable migraine.

In some embodiments, the patient's migraine is refractory migraine.Refractory migraine, as used herein, refers to migraine that fails torespond to pharmacologic treatment. Failure to respond in this regardincludes, for example, failure of a pharmacological treatment toeliminate migraine pain, as well as failure of a pharmacologicaltreatment to reduce severe or moderate migraine pain to mild migrainepain. Refractory migraine may fail to respond one or more types ofpharmacologic treatment. Examples of pharmacologic treatment to whichrefractory migraine may fail to respond include CGRP inhibitors (e.g.,gepants, anti-CGRP antibodies), and triptans (e.g., sumatriptan(Imitrex), rizatriptan (Maxalt), almotriptan (Axert), naratriptan(Amerge), zolmitriptan (Zomig), frovatriptan (Frova) and eletriptan(Relpax)).

In some embodiments of the disclosed methods, the subject's refractorymigraine may fail to respond to CGRP inhibitors, and is referred to asCGRP inhibitor-refractory migraine.

In some embodiments, the subject's CGRP-inhibitor refractory migrainefails to respond to gepant treatment, and is referred to asgepant-refractory migraine. In other embodiments, the subject'sCGRP-inhibitor refractory migraine fails to respond to anti-CGRPantibodies, and is referred to as anti-CGRP antibody-refractorymigraine.

In other embodiments, the subject's refractory migraine may fail torespond to triptans, and is referred to as triptan-refractory migraine.

In other embodiments, the subject's refractory migraine may fail torespond to NSAIDs and is referred to as NSAID-refractory migraine.

In other embodiments, the subject's refractory migraine may fail torespond to dihydroegotamine (DHE) and is referred to as DHE-refractorymigraine.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is epilepsy.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is tremor. In some embodiments, thetremor is essential tremor or Parkinsonian tremor (tremor in personswith Parkinson's disease). In other embodiments, the tremor isorthostatic tremor, primary writing tremor, cerebellar tremor, rubraltremor, neuropathic tremor or dystonic tremor.

EXAMPLES

Example 1: Dissolution and pH Studies

Fospropofol Disodium tablets, 600 mg (label claim; 1.c.), weremanufactured for dissolution testing and use in a pharmacokineticsstudy. A total of three tablets for each lot were weighed prior totesting.

TABLE 1 Acidified Tablets - Compositions A1 A2 A3 A4 Composition mg %w/w mg % w/w mg % w/w mg % w/w Fospropofol 666.9* 42.96 666.9* 42.96666.9* 56.43 666.9* 65.18 Disodium hydrate* Polyplasdone 77.6 5.00 77.65.00 59.1 5.00 51.2 5.00 XL Magnesium 7.8 0.50 7.8 0.50 5.9 0.50 5.10.50 Stearate Citric Acid, 800.0 51.54 monohydrate Ascorbic 800.0 51.54Acid Tartaric Acid 450.0 38.07 Malic Acid. 300.0 29.32 Total 1552.3100.00 1552.3 100.00 1181.9 100.00 1023.2 100.00 *equivalent to 600 mgfospropofol disodium adjusted for water content.

Dissolution studies were performed under the conditions shown in Table 2(n=3 vessels, 300-mL media volume and a single tablet per vessel).Analyses were performed by HPLC under the conditions shown in Table 3.

TABLE 2 Conditions for Dissolution Studies Conditions SettingDissolution Medium 0.1 NHCl de-aerated Apparatus USP apparatus II(rotating paddles) Vessel Volume 300 mL Temperature 37.0° C. ± 0.5° C.Rotation Speed 50 RPM (200 RPM from 60-75 or 60-90 minutes) SampleVolume 1.5 mL Sample Times 5, 10, 15, 20, 25, 30, 40, 45, and 60 minuteswith an infinity pull at 75 or 90 minutes In-line Filter QLA 10 μmPorous (Full Flow) Filters

TABLE 3 HPLC Instrumental Conditions Instrument A suitable gradient HPLCsystem equipped with an inline degasser. Column Phenomenex Luna C18(2),50 × 4.6 mm, 3 um PIN 00B-4251-E0 Detection UV, 220 nm ColumnTemperature 25° C. Sample Temperature Ambient Flow Rate 2.0 mL/minuteInjection Volume 10 μL Run Time 8 minutes (See gradient table below)Mobile Phase A 0.1% TFA in HPW Mobile Phase B 0.1% TFA in ACNColumn/Needle Wash 50:50 ACN:HPW Attenuation 1000 mAUN (when applicable)Gradient Time (min), % A, % B 0.0, 95, 5 6.0, 5, 95 6.2, 95, 5 8.0, 95,5

TABLE 4 A1 (citric acid monohydrate) Dissolution Results for FospropofolDisodium Tablets, 600 mg, (% of label claim recovery) Pull Point(minutes) Vessel 5 10 15 20 25 30 40 45 60 1 10 22 31 42 48 53 61 63 712 10 21 30 38 44 49 55 62 67 3 12 26 36 44 49 54 62 15 71 Average 11 2332 41 4.7 52 59 63 70 SD 1.2 2.6 3.2 3.1 2.6 2.6 3.8 1.5 2.3 % RSD 10.811.5 9.9 7.4 5.6 5.1 6.4 2.4 3.3

TABLE 5 A2 (ascorbic acid) Dissolution Results for Fospropofol DisodiumTablets, 600 mg, (% of label claim recovery) Pull Point (minutes) Vessel5 10 15 20 25 30 40 45 60 1 26 58 76 86 89 90 93 91 92 2 31 62 78 86 9091 93 93 93 3 29 63 78 88 89 91 89 88 91 Average 29 61 77 87 89 91 92 9192 SD 2.5 2.6 1.2 1.2 0.6 0.6 2.3 2.5 1.0 % RSD 8.8 4.3 1.5 1.3 0.6 0.67.5 2.8 1.1

TABLE 6 A3 (tartaric acid) Dissolution Results for Fospropofol DisodiumTablets, 600 mg, (% of label claim recovery) Pull Point (minutes) Vessel5 10 15 20 25 30 40 45 60 1 9 20 28 13 37 41 47 50 54 2 8 18 27 33 37 4046 49 56 3 7 16 24 30 33 37 43 46 52 Average 8 18 26 32 36 39 45 48 54SD 1.0 2.0 2.1 1.7 2.3 2.1 2.1 2.1 2.0 % RSD 12.5 11.1 7.9 5.4 6.5 5.34.6 4.3 3.7

TABLE 7 A4 (malic acid) Dissolution Results for Fospropofol DisodiumTablets, 600 mg, (% of label claim recovery) Pull Point (minutes) Vessel5 10 15 20 25 30 40 45 60 1 21 48 63 70 76 77 82 82 85 2 23 48 59 66 7478 79 81 84 3 23 49 61 67 70 75 77 79 83 Average 22 48 61 68 73 77 79 8184 SD 1.2 0.6 2.0 2.1 3.1 1.5 2.5 1.5 1.0 % RSD 5.2 1.2 3.3 3.1 4.2 2.03.2 1.9 1.2

As used herein, the term “label claim” refers the total weight of thefospropofol disodium within the dosage unit.

FIG. 1 shows the dissolution profiles of the acidified tablets.

The solution pH values after the acidified tablets were dissolved in 300mL of water are shown in Table 8.

TABLE 8 pH After Acidified Tablet Dissolved in 300 mL of Water AcidifierExcipient pH Citric Acid 3.11 Tartaric Acid 3.13 Malic Acid 3.94Ascorbic Acid 4.10

Example 2: Bioavailability Studies

The bioavailability of propofol from the fospropofol-containing dosageforms is assessed in dogs using the following general protocol.

The dogs used in the studies have the following characteristics:

-   -   Strain: Beagle    -   Condition: Purpose-bred, non-naïive    -   Source: Marshall Farms. North Rose, Ny    -   Number of Males: 6 (plus 1 alternate)    -   Target Age at the Initiation of Dosing: At least 8 months.    -   Target Weight at the Initiation of Dosing: 6 to 13 kg

All animals used in the studies have documentation of immunization forparvovirus, distemper, adenovirus type 2, parainfluenza, Bordetella,papilloma, and rabies.

Animals are identified with a tattoo or a subcutaneously implantedelectronic identification chip.

Each animal is inspected by a clinical veterinarian upon receipt.Animals judged to be in good health are placed immediately inacclimation for at least 10 days.

Animals judged to be suitable for testing are assigned to groupsrandomly based on body weight stratification into a block design usingcomputer program. Animals are arbitrarily reassigned to a differentgroup at the discretion of the study director based on acclimation data.

The animals are dosed as follows:

-   -   Dose Route: Tablet; Acidified Tablet    -   Frequency: Once daily; single administration    -   Method: The first day of dosing is designated as Day 1        (exception: alternate animals used for replacement after Day 1        assume the day of the animal being replaced).    -   Tablet Administration: A single dose of the test article is        administered orally via tablet.    -   Each subject receives 1 (600 mg) tablet. Doses are irrespective        of body weight.    -   In studies wherein the dogs are pretreated with pentagstrin, the        pentagastrin is administered intravenously before the dogs are        administered the fospropofol-containing tablet.

In a separate study, the dogs are orally administered a solutioncontaining 30 mg/mL fospropofol at a dose of 160 mg/kg in water ratherthan a tablet.

Bioanalytical Methods:

-   -   Venipuncture from a jugular vein (saphenous or cephalic vein is        used, if necessary).    -   Target Volume (mL): Approximately 1 mL/time point collected        without anesthesia.    -   Anticoagulant: Sodium Heparin    -   Prior to blood collection, approximately 0.05 mL of 200 mg/mL of        sodium orthovanadate (SOV) solution is added to the heparinized        blood collection tubes to prevent ex vivo conversion via        alkaline phosphatase.    -   Special Requirements: After collection, blood collection tubes        are kept on wet ice until centrifugation within 30 minutes of        collection.    -   Processing: Plasma Samples are mixed gently and centrifuged        within 30 minutes of collection. The samples are centrifuged at        2-8° C. and the resultant plasma is separated, transferred to        duplicate uniquely labeled polypropylene tubes, and kept on wet        ice until transferred to storage. Samples are stored in a        freezer set to maintain a target of −70° C.    -   Bioanalytical samples are analyzed for concentration of test        article (fospropofol) and specified metabolites (propofol) using        a validated analytical procedure.

FIG. 2 shows the propofol plasma profile comparisons of (1) 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) with no pentagastrin pretreatment; (2) 600 mg fospropofol disodiumtablet with tartaric acid acidifier (Composition A3) with nopentagastrin pretreatment; and (3) 1300 mg fospropofol disodium aqueoussolution (30 mg/mL) with no pentagastrin pretreatment.

FIG. 3 shows the propofol plasma profile comparisons of (1) 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) with pentagastrin pretreatment; and (2) 600 mg fospropofol disodiumtablet with no acidifier (Control) with pentagastrin pretreatment.

FIG. 4 shows the propofol plasma profile comparisons of (1) 600 mgfospropofol disodium tablet with tartaric acid acidifier (CompositionA3) with no pentagastrin pretreatment; and (2) 600 mg fospropofoldisodium tablet with no acidifier (Control) with pentagastrinpretreatment.

The pharmacokinetic (PK) analysis results are shown in Table 9.

TABLE 9 PK Results AUC_(∞) Cmax (ng/mL) (ng * hr/mL) Half-life (h)(Propofol) (Propofol) (Propofol) 1300 mg Fospropofol disodium aqueoussolution (30 mg/mL) with no pentagastrin pretreatment Mean 399.43 711.061.45 SD 281.70 450.13 0.58 CV 71% 63% 40% 600 mg Fospropofol disodiumtablet with ascorbic acid acidifier (Composition A2) with nopentagastrin pretreatment Mean 714.40 1191.91 1.48 SD 295.70 506.15 0.2CV 41% 42% 14% 600 mg Fospropofol disodium tablet with tartaric acidacidifier (Composition A3) with no pentagastrin pretreatment Mean1107.50 1656.87 2.93 SD 685.43 998.42 3.10 CV 62% 60% 106% 600 mgFospropofol disodium tablet with control (i.e., no acidifier) withpentagastrin pretreatment Mean 732.5 1002.22 1.34 SD 312.47 340.86 0.34CV 43% 34% 26% 600 mg Fospropofol disodium tablet with ascorbic acidacidifier (Composition A2) with pentagastrin pretreatment Mean 928.331623.93 3.84 SD 167.12 378.36 3.22 CV 18% 23% 84%

The pharmacokinetic results demonstrate that administering fospropofoltogether with an acid, such as in the acidified tablets, results inincreased propofol Cmax and AUC_(∞) when compared to the dose adjustedexposure seen with the oral solution. See FIG. 2; Table 9. This effectis seen using both ascorbic acid and tartaric acid as the tabletacidifiers.

In addition, the results demonstrate that administration of theacidified tablets with pentagastrin pretreatment results in increasedplasma propofol Cmax and AUC_(∞) compared to the plasma propofol Cmaxand AUC_(∞) observed upon administration of a control tablet (i.e., withno acidifier) with pentagastrin pretreatment. See FIG. 3; Table 9.Pentagastrin pretreatment acidifies the subject's stomach contents to anacidity comparable to that of normal human stomach contents.

In addition, these results demonstrate that co-administration offospropofol disodium with tartaric acid without pentagastrinpretreatment results in increased plasma propofol Cmax and AUC_(∞)compared to the plasma propofol Cmax and AUC_(∞) observed uponadministration of a control tablet (i.e., with no acidifier) withpentagastrin pretreatment. See FIG. 4; Table 9.

The experiments described above surprisingly demonstrate that oraladministration of fospropofol together with a pharmaceuticallyacceptable acid increases the plasma propofol Cmax and AUC_(∞) relativeto controls in which fospropofol is orally administered without anacidifier. Moreover, this effect is seen with multiple acids (e.g.,ascorbic acid, tartaric acid) and is seen under conditions expected inhuman subjects. Thus, the disclosed invention solves the problem ofproviding an oral dosage form that can provide useful propofolpharmacokinetics.

These results also demonstrate that co-administration of fospropofoldisodium with a pharmaceutically acceptable acid can result in decreasedvariability in Cmax and AUC_(∞) relative to administration without acid.

In a separate study, the food effect upon administering the compositionsof the disclosure is examined. Two groups of dogs, one fasted and onefed, are administered either the 600 mg fospropofol acidifiedcomposition comprising ascorbic acid (i.e., composition A2) or 600 mg(3×200 mg) of fospropofol control composition (i.e., HMPC capsule; noacidifier). The fasted group is fasted (no food, only water) overnightprior to being administered the fospropofol dose. The maximum individualfasting period does not exceed 24 hours. The fasted group is pretreatedwith pentagastrin. The fed group is given a high calorie meal and thedose of fospropofol is given within an hour of eating the meal. The fedgroup is not pretreated with pentagastrin.

TABLE 10 Food Effect Study Total Fospropofol (fospropofol + FospropofolPropofol propofol) Cmax AUC∞ Cmax Mean AUC_(0-∞) Composition (ng/mL)(ng * hr/mL) (ng/mL) (mol * h/mL) Ascorbic Acid fasted 21433 18986 9286.2779 × 10⁻⁰⁸ Ascorbic Acid fed 21914 13968 573 4.4435 × 10⁻⁰⁸Fed/Fasted ratio 1.02 0.74 0.62 0.71 Control fasted 18300 15013 6474.7778 × 10⁻⁰⁸ Control fed 3131 4313 193 1.4223 × 10⁻⁰⁸ Fed/Fasted ratio0.17 0.29 0.30 0.30

These results demonstrate that the acidified compositions demonstrate afood effect and that the food effect differs from that observed with thenon-acidified control composition. See FIG. 5; Table 10.

Both the acidified tablet and the control composition exhibit a negativefood effect on the bioavailability of fospropofol.

The extent of the food effect is modulated depending on the dosage form.

In the control compositions, the mean fospropofol Cmax (fed) is 17% ofthe mean fospropofol Cmax (fasted). In the acidified tablet, the meanfospropofol Cmax (fed) is 102% of the mean fospropofol Cmax (fasted).

In the control compositions, the mean total fospropofol Cmax (fed) is30% of the mean total fospropofol Cmax (fasted). In the acidifiedtablet, the mean total fospropofol Cmax (fed) is 71% of the mean totalfospropofol Cmax (fasted).

Thus, as these results show, the acidified fospropofol compositionreduces the negative food effect.

In some embodiments, the disclosure is directed to the followingaspects:

Aspect 1. A pharmaceutical dosage form for oral administrationcomprising fospropofol or a pharmaceutically acceptable salt thereof, apharmaceutically acceptable acid.

Aspect 2. The pharmaceutical dosage form according to aspect 1comprising fospropofol.

Aspect 3. The pharmaceutical dosage form according to aspect 1comprising a pharmaceutically acceptable salt of fospropofol.

Aspect 4. The pharmaceutical dosage form according to aspect 3, whereinthe pharmaceutically acceptable salt of fospropofol is fospropofoldisodium.

Aspect 5. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the pharmaceutically acceptable acid is onthe FDA inactive ingredient database (IID) for approved drug products orgenerally recognized as safe (GRAS).

Aspect 6. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the pharmaceutically acceptable acid is1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxethanesulfonic acid, 4-acetamidobenzoic acid, 4-aminosalicyclicacid, acetic acid, aceturic acid, Acid hydrolyzed proteins, AcidModified Starch, Aconitic Acid, adipic acid, alginic acid,a-oxo-glutaric acid, benzenesulfonic acid, benzoic acid, butyric acid,camphor-10-sulfonic acid, camphoric acid, capric acid, caproic acid,caprylic acid, carbonic acid, Cholic acid, cinnamic acid, citric acid,cyclamic acid, D(−)-Lactic acid, Desoxycholic acid, D-glucaric acid,D-glucoheptonic acid, D-glucuronic acid, Di(tert-butyl)naphthalenedisulfonic acid, Di(tert-butyl)naphthalenesulfonic acid,DL-lactic acid, DL-mandelic acid, DL-tartaric acid, tartaric acid,dodecylsulfuric acid, Erythorbic acid (D-isoascorbic acid),ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glutaric acid, glycerophosphoricacid, Glycocholic acid, glycolic acid, hexanedioic acid, hippuric acid,hydrobromic acid, Hydrochloric acid, Iron naphthenate, iron salts, ironsalts, isobutyric acid, L(+)-lactic acid, L(+)-potassium acid tartrate,L(+)-tartaric acid, Lactic acid, lactobionic acid, L-ascorbic acid,ascorbic acid, L-aspartic acid, lauric acid, L-glutamic acid, L-Glutamicacid hydrochloride, Linoleic acid, L-Malic acid, L-pyroglutamic acid,L-tartaric acid, maleic acid, malic acid, malonic acid, methanesulfonicacid, monobasic potassium phosphate, monobasic sodium phosphate,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, naphthenicacids, Niacin (nicotinic acid), nicotinic acid, nitric acid, octanoicacid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,Pectin low acid, Pectinic acid, phosphoric acid, propanoic acid,Propionic acid, p-toluenesulfonic acid, pyruvic acid, saccharin,salicylic acid, sebacic acid, Sodium acid pyrophosphate, Sodium aluminumphosphate, sodium metabisulfite, Sorbic acid, stearic acid, succinicacid, sulfuric acid, tall oil fatty acids, Tannic acid (hydrolyzablegallotannins), Taurocholic acid, thiocyanic acid, Thiodipropionic acid,trifluoroacetic acid, undec-10-enoic acid, orange juice, apple juice,grapefruit juice, or a combination thereof or a combination thereof.

Aspect 7. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the pharmaceutically acceptable acid isascorbic acid, citric acid, malic acid, or tartaric acid.

Aspect 8. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the pharmaceutically acceptable acid isascorbic acid.

Aspect 9. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the pharmaceutically acceptable acid istartaric acid.

Aspect 10. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the pharmaceutically acceptable acid iscitric acid.

Aspect 11. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the pharmaceutically acceptable acid is malicacid.

Aspect 12. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of water at 25° C.results in a solution having a pH of 6.3 or less.

Aspect 13. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of water at 25° C.results in a solution having a pH of 4.5 or less.

Aspect 14. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of water at 25° C.results in a solution having a pH of 4.2 or less.

Aspect 15. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of water at 25° C.results in a solution having a pH of 4.0 or less.

Aspect 16. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of 0.1 N HC1 at 37°C., results in at least 30% of the fospropofol or pharmaceuticallyacceptable salt thereof (on a fospropofol basis) in the dosage formbeing released from the dosage form within 60 minutes.

Aspect 17. The pharmaceutical dosage form according to aspect 16,wherein dissolution of an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HC1 at 37° C. results in atleast 30% of the fospropofol or pharmaceutically acceptable salt thereof(on a fospropofol basis) in the dosage form being released from thedosage form within 30 minutes.

Aspect 18. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of 0.1 N HC1 at 37°C. results in at least 50% of the fospropofol or pharmaceuticallyacceptable salt thereof (on a fospropofol basis) in the dosage formbeing released from the dosage form within 60 minutes.

Aspect 19. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of 0.1 N HC1 at 37°C. results in at least 50% of the fospropofol or pharmaceuticallyacceptable salt thereof (on a fospropofol basis) in the dosage formbeing released from the dosage form within 30 minutes.

Aspect 20. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of 0.1 N HC1 at 37°C. results in at least 90% of the fospropofol or pharmaceuticallyacceptable salt thereof (on a fospropofol basis) in the dosage formbeing released from the dosage form within 30 minutes.

Aspect 21. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of 0.1 N HC1 at 37 °C. results in at least 90% of the fospropofol or pharmaceuticallyacceptable salt thereof (on a fospropofol basis) in the dosage formbeing released from the dosage form within 60 minutes.

Aspect 22. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein dissolution of an amount of the dosage formcontaining a therapeutically effective amount of fospropofol, or apharmaceutically acceptable salt thereof, in 300 mL of 0.1 N HC1 at 37 °C. results in release of at least 90% of the fospropofol from the dosageform within 30 minutes.

Aspect 23. The pharmaceutical dosage form according to any one of thepreceding aspects, wherein the mole ratio of fospropofol or apharmaceutically acceptable salt thereof (on a fospropofol basis) topharmaceutically acceptable acid is 3:1 or less.

Aspect 24. A method of administering fospropofol or a pharmaceuticallyacceptable salt thereof to a subject in need thereof, comprising orallyadministering to said subject a pharmaceutical dosage form according toany one of the preceding aspects.

Aspect 25. A method of administering fospropofol or a pharmaceuticallyacceptable salt thereof to a subject in need thereof, said methodcomprising orally administering fospropofol, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable acid, to thesubject.

Aspect 26. The method of aspect 24 or aspect 25, wherein saidfospropofol, or a pharmaceutically acceptable salt thereof, and saidpharmaceutically acceptable acid are present in the same unit dosageform.

Aspect 27. The method of aspect 25, wherein all or a portion of saidpharmaceutically acceptable acid is administered separately from theunit dosage form comprising said fospropofol, or a pharmaceuticallyacceptable salt thereof.

Aspect 28. The method according to any one of aspects 24 to 27, whereinsaid pharmaceutically acceptable acid is ascorbic acid, citric acid,malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid,lactic acid, monobasic sodium phosphate, monobasic potassium phosphate,sodium metabisulfite, apple juice, orange juice, or grapefruit juice.

Aspect 29. The method according to aspect 28, wherein saidpharmaceutically acceptable acid is ascorbic acid, citric acid, malicacid, or tartaric acid.

Aspect 30. The method according to aspect 29, wherein saidpharmaceutically acceptable acid is ascorbic acid.

Aspect 31. The method according to aspect 29, wherein saidpharmaceutically acceptable acid is citric acid.

Aspect 32. The method according to aspect 29, wherein saidpharmaceutically acceptable acid is malic acid.

Aspect 33. The method according to aspect 29, wherein saidpharmaceutically acceptable acid is tartaric acid.

Aspect 34. The method of any one of aspects 24 to 33, wherein saidsubject is experiencing hypochlorhydria or achlorhydria prior to theadministration.

Aspect 35. The method according to aspect 34, wherein said subject hasbeen administered a proton pump inhibitor (PPI) prior to theadministration.

Aspect 36. The method of any one of aspects 24 to 35, wherein saidadministration results in a propofol Cmax that is greater than apropofol Cmax resulting from administering fospropofol, or apharmaceutically acceptable salt thereof, without administration of thepharmaceutically acceptable acid.

Aspect 37. The method of aspect 36, wherein the propofol Cmax is atleast 1.5 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

Aspect 38. The method of aspect 36, wherein the propofol Cmax is atleast 2 times greater than a propofol Cmax resulting from administeringfospropofol, or a pharmaceutically acceptable salt thereof, withoutadministration of the pharmaceutically acceptable acid.

Aspect 39. The method of aspect 36, wherein the propofol Cmax is atleast 2.5 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

Aspect 40. The method of aspect 36, wherein the propofol Cmax is atleast 3 times greater than a propofol Cmax resulting from administeringfospropofol, or a pharmaceutically acceptable salt thereof withoutadministration of the pharmaceutically acceptable acid.

Aspect 41. The method of any one of aspects 24 to 40, wherein saidadministration results in a propofol AUC_(∞) that is greater than apropofol AUC_(∞) resulting from administering fospropofol, or apharmaceutically acceptable salt thereof, without administration of thepharmaceutically acceptable acid.

Aspect 42. The method of aspect 41, wherein the propofol AUC_(∞) is atleast 1.5 times greater than a propofol AUC_(∞) resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

Aspect 43. The method of aspect 41, wherein the propofol AUC_(∞) is atleast 2 times greater than a propofol AUC_(∞) resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

Aspect 44. The method of aspect 41, wherein the propofol AUC_(∞) is atleast 2.5 times greater than a propofol AUC_(∞) resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

Aspect 45. The method of aspect 41, wherein the propofol AUC_(∞) is atleast 3 times greater than a propofol AUC_(∞) resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without co-administration of the pharmaceutically acceptableacid.

Aspect 46. The method of any one of aspects 24 to 45, wherein saidmethod is directed to treating a disease or disorder in a subject inneed thereof.

Aspect 47. The method of aspect 46, wherein said method comprises orallyadministering to a subject the pharmaceutical dosage form of any one ofaspects 1 to 23.

Aspect 48. The method of aspect 46, comprising orally administeringfospropofol, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable acid, to a subject.

Aspect 49. The method of any one of aspects 46 to 48, wherein thedisease or disorder is migraine, acute repetitive seizures, seizureclusters, neuropathic pain, postherpetic neuralgia, traumatic braininjury, Alzheimer's disease, epilepsy, anxiety, fragile X syndrome,post-traumatic stress disorder, lysosomal storage disorders(Niemann-Pick type C disease), depression (including post-partumdepression), premenstrual dysphoric disorder, alcohol craving, orsmoking cessation.

Aspect 50. The method of aspect 49, wherein the disease or disorder ismigraine.

What is claimed:
 1. A method of treating migraine in a subject in needthereof, said method comprising orally administering to said subject apharmaceutical dosage form comprising fospropofol disodium, and apharmaceutically acceptable acid, wherein the administration results ina plasma fospropofol Cmax (fed) that is at least 30% of thecorresponding plasma fospropofol Cmax (fasted).
 2. The method accordingto claim 1, wherein the administration results in a plasma fospropofolCmax (fed) that is at least 90% of the corresponding plasma fospropofolCmax (fasted).
 3. The method according to claim 1, wherein thepharmaceutically acceptable acid is ascorbic acid, citric acid, malicacid, or tartaric acid.
 4. The method according to claim 1, wherein thepharmaceutically acceptable acid is ascorbic acid.
 5. The methodaccording to claim 1, wherein the pharmaceutically acceptable acid istartaric acid.
 6. The method according to claim 1, wherein thepharmaceutically acceptable acid is citric acid.
 7. The method accordingto claim 1, wherein the pharmaceutically acceptable acid is malic acid.8. The method according to claim 1, wherein said subject is a human. 9.A method of treating migraine in a subject in need thereof, said methodcomprising orally administering to said subject a pharmaceutical dosageform comprising fospropofol disodium, and a pharmaceutically acceptableacid, wherein the administration results in a plasma total fospropofolAUC_(∞) (fed) that is at least 40% of the corresponding plasma totalfospropofol AUC_(∞) (fasted).
 10. The method according to claim 9,wherein the administration results in a plasma total fospropofol AUC_(∞)(fed) that is at least 70% of the corresponding plasma total fospropofolAUC_(∞) (fasted).
 11. The method according to claim 9, wherein thepharmaceutically acceptable acid is ascorbic acid, citric acid, malicacid, or tartaric acid.
 12. The method according to claim 9, wherein thepharmaceutically acceptable acid is ascorbic acid.
 13. The methodaccording to claim 9, wherein the pharmaceutically acceptable acid istartaric acid.
 14. The method according to claim 9, wherein thepharmaceutically acceptable acid is citric acid.
 15. The methodaccording to claim 9, wherein the pharmaceutically acceptable acid ismalic acid.
 16. The method according to claim 9, wherein said subject isa human.